Abstract A024: SOX11: An <i>Achilles heel</i> of mantle cell lymphoma enhancing sensitivity to DNA damaging agents by impairing DNA repair
Notice bibliographique
Résumé
Abstract Mantle cell lymphoma (MCL) is an aggressive malignancy with mature B-cell differentiation and a median overall survival of 5 years. A characteristic hallmark of MCL is the aberrant expression of the transcription factor sex determining region on Y chromosome (SRY)-related and high mobility group (HMG) domain containing protein 11 (SOX11) in approximately 90% of the cases. The role of SOX11 in MCL pathogenesis has been attributed to transcriptional dysregulation, ultimately driving malignant gene expression profile of MCL. However, little is known about the potential transcription factor-independent modes of action of SOX11. Our co-immunprecipitation and proteomic analysis showed that SOX11 binds to factors of DNA damage response (DDR), nucleosome remodeling and chromatin regulation, among others. Sterile Alpha motif and HD domain containing protein 1 (SAMHD1) is top-listed among the SOX11 binding partners in MCL. We recently showed that SOX11 binds via its HMG domain to SAMHD1, disturbing its homo-tetramerization. A growing body of evidence unveiled the implication of SAMHD1 in DDR, particularly in promoting homologous recombination. Immunofluorescent imaging showed that SOX11 impairs homologous recombination in MCL, evidenced by reduced accumulation of RAD51 foci upon chromatin in response to treatment with the topoisomerase1 inhibitor camptothecin (CPT). This was further consistent with abrogated phosphorylation of DNA-break binding protein RPA32 (S4/8), but not total RPA32, in response to CPT treatment in SOX11-positive conditions. Inducing SOX11 expression in SOX11-negative MCL cell line (JVM-2) resulted in increased accumulation of cytosolic single-stranded DNA upon CPT treatment. This was translated in an enhanced sensitivity to CPT in SOX11-expressing MCL cell lines as compared to SOX11-negative conditions. Moreover, this enhanced sensitivity was reflected in increased levels of cleaved PARP1, cleaved caspase 3 and persistent γ-H2A.X in SOX11-positive cells. Simian Immunodeficiency Virus protein (Vpx)-mediated depletion of SAMHD1 yielded a similar, yet attenuated, sensitive phenotype to CPT compared to SOX11 induction in JVM-2. SAMHD1 depletion in addition to SOX11 induction showed no significant additional impact on the response to CPT in JVM-2 under the conditions tested. Intriguingly, T592 phosphorylation of SAMHD1 was reduced upon inducing SOX11 expression in JVM-2, suggesting a mode of action by which SOX11 inhibits SAMHD1. However, the mechanism behind increased levels of SAMHD1 post-translational modification upon SOX11 induction requires further investigation. Altogether, our findings suggest that SOX11 may impair homologous recombination, at least in part, through inhibiting SAMHD1. These results highlight SOX11 as an Achilles heel that renders MCL vulnerable to DNA damaging and suggest that incorporating DNA damaging agents including topoisomerase inhibitors or anthracyclines into currently used treatment modalities for MCL might be clinically beneficial. Citation Format: HA Morsy, Virginia Amador, Birger Christensson, Nikolas Herold, Birgitta Sander. SOX11: An Achilles heel of mantle cell lymphoma enhancing sensitivity to DNA damaging agents by impairing DNA repair [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A024.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».